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Details

Autor(en) / Beteiligte
Titel
miR-33a promotes glioma-initiating cell self-renewal via PKA and NOTCH pathways
Ist Teil von
  • The Journal of clinical investigation, 2014-10, Vol.124 (10), p.4489-4502
Ort / Verlag
United States: American Society for Clinical Investigation
Erscheinungsjahr
2014
Link zum Volltext
Quelle
MEDLINE
Beschreibungen/Notizen
  • Glioblastoma (GBM) is the most common and lethal brain tumor in adults. Glioma-initiating cells (GICs) are stem-like cells that have been implicated in glioblastoma progression and recurrence; however, the distinct properties of GICs and non-GICs within GBM tumors are largely uncharacterized. Here, we evaluated stem cell-associated microRNA (miR) expression in GICs from GBM patients and GICs derived from xenografted human glioma cell lines and determined that miR-33a promotes GIC growth and self-renewal. Moreover, evaluation of a GBM tissue array revealed that higher miR-33a expression was associated with poor prognosis of GBM patients. Antagonizing miR-33a function in GICs reduced self-renewal and tumor progression in immune-compromised mice, whereas overexpression of miR-33a in non-GICs promoted the display of features associated with GICs. We identified the mRNAs encoding phosphodiesterase 8A (PDE8A) and UV radiation resistance-associated gene (UVRAG) as direct miR-33a targets. PDE8A and UVRAG negatively regulated the cAMP/PKA and NOTCH pathways, respectively; therefore, miR-33a-dependent reduction of these proteins promoted growth and self-renewal of GICs by enhancing PKA and NOTCH activity. Furthermore, in GBM specimens, there was an inverse correlation between the expression levels of miR-33a and PDE8A and UVRAG expression. These findings reveal a miR-33a-centered signaling network that promotes GIC maintenance and has potential as a therapeutic target for GBM treatment.

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